The proposed study will extend an innovative investigation of biologic markers for autism using archived prenatal and newborn specimens from mother-baby pairs. Funded by the NIMH (R01 MH72565) for an initial three-year period, this project, known as the Early Markers for Autism (EMA) Study, is the first large, population-based case-control study to utilize these very early biologic specimens to elucidate underlying causes of autism. The study includes three groups: children with autism spectrum disorders (ASD), children with mental retardation (MR) but not autism, and children selected at random from the general population (GP). The scientific and conceptual focus of the EMA Study is on immunologic and genetic susceptibility factors, environmental exposures, and the interplay of genes with environment, operating either directly on neurodevelopment, or indirectly via dysregulation of the immune system. Preliminary results from the first funding cycle indicate that the mid-pregnancy immune profile of mothers of children with ASD is dysregulated in comparison to mothers of control children. Levels of select cytokines (IFN-gamma, IL-4, IL-5, IL-6) are elevated, and maternal antibodies to fetal brain proteins are present more often in case than control mothers. In addition, polymorphisms in select immune function genes are more common in mothers (IFN-gamma) and children (IL-6) with autism. This application seeks funding to further these initial findings by conducting a much larger case-control study among a new sample of 1,200 mother-baby pairs (400 ASD, 400 MR, 400 GP controls), with an added family-based component that includes 60 siblings of ASD cases and 60 siblings of MR controls. Funding to assemble this new study cohort has already been received by Autism Speaks and the study cohort will be assembled by September 2009. In this application, maternal mid-pregnancy specimens will be analyzed for polyfluoroalkyl compounds (PFCs), ubiquitous persistent organic compounds that have developmental toxicity and are likely endocrine disruptors. This large sample size will ensure sufficient statistical power for the examination of relatively rare exposures and phenotypic subgroups of ASD. Findings from this study will likely define areas for further investigations of physiologic mechanism and will provide normative data on unaffected controls. In the long-term, a better understanding of the underlying biology may suggest appropriate strategies for early intervention and contribute to the eventual prevention of this often devastating and usually life-long disability. PUBLIC HEALTH RELEVANCE: The primary goal of this study is to identify early biologic markers for ASD. We will use existing blood specimens taken during pregnancy to explore the interplay between markers of endocrine function and environmental exposures during critical periods of fetal brain development and identify factors that contribute to ASD risk. In the long-term, a better understanding of the underlying biology may suggest appropriate strategies for early intervention and contribute to the eventual prevention of this often devastating and usually life-long disability.